The National Toxicology Program (NTP) found "equivocal evidence" of a link between fluoride ingestion and the formation of osteosarcoma in a small percentage of male rats that received high doses of fluoridated water. The HHS Committee to Coordinate Environmental Health and Related Programs (CCEHRP) reported that males under 20 (the gender and age group with the highest incidence) living in the 12 fluoridated counties had a 79 percent increase in osteosarcomas while a similar age/gender group in the 21 non-fluoridated counties experienced a 4 percent decrease in the osteosarcoma rate between 1973-80 to 1981-1987 in a correlational study. In direct response to a CCEHRP research recommendation, the proposed study will assess the risk for osteosarcoma from the ingestion of fluoridated water. A nation-wide hospital based case-control study will be conducted on 320 prevalent cases and 320 incident cases over a 3 1/2 year period. A ratio of 1:2 cases to controls matched by age (+/- 3 years), gender, and state of residence will be recruited from the orthopedic departments from eight tertiary care centers distributed throughout the nation. A telephone interview will obtain the complete residential fluoride histories and exposure to fluoride from oral hygiene practices. Additionally, fluoride content of the bone and toenails from incident cases will be compared to matched controls. Solid-state NMR techniques will assess the level of fluoride in the bone. Neutron activation for elemental analysis will assess the level of fluoride in toe nail clippings as a cumulative measure of fluoride intake. We will test the primary hypothesis that higher fluoride exposure is associated with the risk of osteosarcoma. An incorrect inference implicating systemic fluoride carcinogenicity and its removal from our water systems under the EPA Delaney clause would have significant oral health consequences for most Americans, particularly those who cannot afford to pay for increasingly expensive restorative dental care.